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Despite the increasing role of molecular markers, differential counts and morphology of hematopoietic cells in the bone marrow (BM) remain essential diagnostic criteria in hematological diseases. However, the respective reference values for BM myelogram commonly used came from small series with limited numbers of healthy individuals. We evaluated the myelograms of 236 healthy individuals who underwent unrelated bone marrow donation. Health check-ups were performed 4 weeks prior to harvest. Samples for this study, taken from the first aspiration, were stained according to the standard Pappenheim method. Three experienced investigators assessed cellularity, megakaryopoiesis, and differential counts independently. The median donor age was 31 (range 18–51) years. Predonation tests did not reveal any relevant morbidity. Thirty-seven out of 42 hypocellular marrow samples were from younger donors up to 39 years. Content of megakaryocytes was normal in 210 specimens (89%). Gender and body mass index had significant impact on hematopoiesis, whereas age had not. The number of erythroblasts was higher (about 32%) and the proportion granulopoiesis slightly lower (about 50%) compared with previous studies. Differential counts showed also some differences with respect to individual maturation stages in these lines. Interrater comparisons showed greater reliability for the assignment of cells to the different hematopoietic cell lines than for single-cell diagnoses. This study largely confirms the results for cell counts in normal human bone marrow available from previous reports and provides some insights into factors that affect individual cell populations. It also reveals substantial variability among even experienced investigators in cytological diagnoses.

The graft-versus-leukemia (GVL) effect after allogeneic hematopoietic cell transplant (HCT) can prevent relapse but the risk of severe graft-versus-host disease (GVHD) leads to prolonged intensive immunosuppression and possible blunting of the GVL effect. Strategies to reduce immunosuppression in order to prevent relapse have been offset by increases in severe GVHD and nonrelapse mortality (NRM). We recently validated the MAGIC algorithm probability (MAP) that predicts the risk for severe GVHD and NRM in asymptomatic patients using serum biomarkers. In this study we tested whether the MAP could identify patients whose risk for relapse is higher than their risk for severe GVHD and NRM. The multicenter study population (n = 1604) was divided into two cohorts: historical (2006–2015, n = 702) and current (2015–2017, n = 902) with similar NRM, relapse, and survival. On day 28 post-HCT, patients who had not developed GVHD (75% of the population) and who possessed a low MAP were at much higher risk for relapse (24%) than severe GVHD and NRM (16 and 9%); this difference was even more pronounced in patients with a high disease risk index (relapse 33%, NRM 9%). Such patients are good candidates to test relapse prevention strategies that might enhance GVL.

We conducted a prospective clinical trial to investigate the safety and efficacy of plerixafor (P) in allogeneic peripheral blood stem cells (PBSC) donors with poor mobilization response to standard-dose granulocyte colony-stimulating factor (G-CSF), defined by <2 × 106 CD34 + cells/kg recipient body-weight (CD34+/kg RBW) after 1st apheresis. A single dose of 240 µg/kg P was injected subcutaneously at 10 p.m. on the day of the 1st apheresis. Thirty-seven allogeneic PBSC donors underwent study treatment. The median CD34+ count in peripheral blood was 15/µl on Day 1 after G-CSF alone, versus 44/µl on Day 2 after G-CSF plus P (p < 0.001). The median yield of CD34+ cells was 1.1 × 108 on Day 1 and 2.8 × 108 on Day 2. In contrast to a median yield of only 1.31 × 106 CD CD34+/kg RBW on Day 1, triggering study inclusion, a median of 3.74 × 106 CD CD34+/kg RBW were collected with G-CSF plus P on Day 2. Of 37 donors, 21 reached the target cell count of >4.5 × 106 CD34+/kg RBW (57%, 95%CI 40–73%). No donor experienced a severe adverse event requiring treatment. In conclusion, P might be considered on a case-by-case basis for healthy allogeneic donors with very poor stem cell mobilization success after G-CSF.

Chorea-Acanthocytosis (ChAc) is a devastating, little understood, and currently untreatable neurodegenerative disease caused by VPS13A mutations. Based on our recent demonstration that accumulation of activated Lyn tyrosine kinase is a key pathophysiological event in human ChAc cells, we took advantage of Vps13a −/− mice, which phenocopied human ChAc. Using proteomic approach, we found accumulation of active Lyn, γ-synuclein and phospho-tau proteins in Vps13a −/− basal ganglia secondary to impaired autophagy leading to neuroinflammation. Mice double knockout Vps13a −/− Lyn −/− showed normalization of red cell morphology and improvement of autophagy in basal ganglia. We then in vivo tested pharmacologic inhibitors of Lyn: dasatinib and nilotinib. Dasatinib failed to cross the mouse brain blood barrier (BBB), but the more specific Lyn kinase inhibitor nilotinib, crosses the BBB. Nilotinib ameliorates both Vps13a −/− hematological and neurological phenotypes, improving autophagy and preventing neuroinflammation. Our data support the proposal to repurpose nilotinib as new therapeutic option for ChAc patients.

BackgroundThe combination of dexamethasone, high-dose cytarabine, and cisplatin (DHAP) is an established salvage regimen for lymphoma patients. We hypothesized that a modified administration schedule for cisplatin and cytarabine results in lower toxicity and improved efficacy.MethodsWe retrospectively analysed 119 patients with relapsed or refractory, aggressive, or indolent B-cell lymphomas, mantle-cell lymphomas, peripheral T-cell lymphomas, or Hodgkin’s lymphomas who were treated with the modified DHAP (mDHAP) regimen (dexamethasone 40 mg 15 min-i.v. infusion, days 1–4; cytarabine 2 × 0.5 g/m2 1 h-i.v. infusion, days 1–4; cisplatin 25 mg/m2 24 h-i.v. infusion, days 1–4). Responding and eligible patients underwent stem-cell transplantation.ResultsIn total, 185 treatment cycles were evaluable. Severe myelosuppression was the main toxicity occurring in 90% of the cycles. Febrile neutropenia or documented infection was found in less than 40%. Two patients died related to treatment (TRM, 1.7%). Nephrotoxicity did not exceed CTC grade 3, which occurred in four cycles only (2.2%). Complete (CR) or partial (PR) responses after mDHAP were documented in 16% and 39% (overall response rate 55%). Harvest of autologous stem cells was successful in 94 (79%) patients and 85 patients (71%) proceeded to stem-cell transplantation. The median overall and progression-free survival was 50.8 and 25.8 months.ConclusionsAn improvement in efficacy could not be observed after modified DHAP regimen; however, manageable toxicity and reduced renal complications suggest further investigation. The study, however, also underlines the need for new concepts in the management of advanced and high-risk lymphomas.

Alloantigen expression on host antigen-presenting cells (APCs) is essential to initiate graft-versus-host disease (GvHD); therefore, alloantigen expression on host target epithelium is also thought to be essential for tissue damage. We tested this hypothesis in mouse models of GvHD using bone-marrow chimeras in which either major histocompatibility complex class I or class II alloantigen was expressed only on APCs. We found that acute GvHD does not require alloantigen expression on host target epithelium and that neutralization of tumor necrosis factor-α and interleukin-1 prevents acute GvHD. These results pertain particularly to CD4-mediated GvHD but also apply, at least in part, to CD8-mediated GvHD. These results challenge current paradigms about the antigen specificity of GvHD effector mechanisms and confirm the central roles of both host APCs and inflammatory cytokines in acute GvHD.

Lenalidomide (LEN) leads to erythroid improvement in the majority of patients with myelodysplastic syndrome and isolated deletion of the long arm of chromosome 5 (MDS-del(5q)). This effect is believed to be exerted via its immunomodulatory properties, although the precise nature is still incompletely understood. We prospectively performed immune profiling in the bone marrow and blood of MDS-del(5q) patients undergoing LEN therapy for a median of 6 cycles. Therapy with LEN led to a significant increase in the median absolute lymphocyte count (1.3-fold, p  = 0.013) without changes in the distribution of the T helper cells within the entire compartment. In parallel, the frequency of Treg increased significantly during treatment both in the peripheral blood (5.0 vs. 9.6 %, p  = 0.001) and bone marrow (3.4 vs. 8.1 %, p  = 0.001). Surprisingly, LEN treatment led to a decrease in TGFbeta levels, both in the peripheral blood (4.9 vs. 2.3 ng/ml, p  = 0.039) and bone marrow (4.5 vs. 0.8 ng/ml, p  = 0.023). These changes were not associated with an increase in pro-inflammatory Th17 cells. Taken together, our results demonstrate that LEN induces a shift in lymphocytic populations towards immunosuppression in MDS-del(5q) patients.

Chorea-acanthocytosis (ChAc) is a neurodegenerative disease caused by mutations in the VPS13A gene. It is characterized by several neurological symptoms and the appearance of acanthocytes. Elevated tyrosine kinase Lyn activity has been recently identified as one of the key pathophysiological mechanisms in this disease, and therefore represents a promising drug target. Methods: We evaluated an individual off-label treatment with the tyrosine kinase inhibitor dasatinib (100 mg/d, 25.8–50.4 weeks) of three ChAc patients. Alongside thorough safety monitoring, we assessed motor and non-motor scales (e.g., MDS-UPDRS, UHDRS, quality of life) as well as routine and experimental laboratory parameters (e.g., serum neurofilament, Lyn kinase activity, actin cytoskeleton in red blood cells). Results: Dasatinib appeared to be reasonably safe. The clinical parameters remained stable without significant improvement or deterioration. Regain of deep tendon reflexes was observed in one patient. Creatine kinase, serum neurofilament levels, and acanthocyte count did not reveal consistent effects. However, a reduction of initially elevated Lyn kinase activity and accumulated autophagy markers, as well as a partial restoration of the actin cytoskeleton, was found in red blood cells. Conclusions: We report on the first treatment approach with disease-modifying intention in ChAc. The experimental parameters indicate target engagement in red blood cells, while clinical effects on the central nervous system could not be proven within a rather short treatment time. Limited knowledge on the natural history of ChAc and the lack of appropriate biomarkers remain major barriers for “clinical trial readiness”. We suggest a panel of outcome parameters for future clinical trials in ChAc.

Despite major improvements in allogeneic hematopoietic cell transplantation over the last decades, corticosteroid-refractory (SR) acute (a) and chronic (c) graft-versus-host disease (GVHD) cause high mortality. Pre-clinical evidence indicates the potent anti-inflammatory properties of the JAK1/2 inhibitor ruxolitinib. In this retrospective survey, 19 stem cell transplant centers in Europe and the United States reported outcome data from 95 patients who had received ruxolitinib as salvage-therapy for SR-GVHD. Patients were classified as having SR-aGVHD (n=54, all grade III or IV) or SR-cGVHD (n=41, all moderate or severe). The median number of previous GVHD-therapies was 3 for both SR-aGVHD (1–7) and SR-cGVHD (1–10). The ORR was 81.5% (44/54) in SR-aGVHD including 25 CRs (46.3%), while for SR-cGVHD the ORR was 85.4% (35/41). Of those patients responding to ruxolitinib, the rate of GVHD-relapse was 6.8% (3/44) and 5.7% (2/35) for SR-aGVHD and SR-cGVHD, respectively. The 6-month-survival was 79% (67.3%–90.7%,95% CI) and 97.4% (92.3%–100%,95% CI) for SR-aGVHD and SR-cGVHD, respectively. Cytopenia and CMV-reactivation were observed during ruxolitinib-treatment in both SR-aGVHD (30/54, 55.6% and 18/54, 33.3%) and SR-cGVHD (7/41, 17.1% and 6/41, 14.6%) patients. Ruxolitinib may constitute a promising new treatment option for SR-aGVHD and SR-cGVHD that should be validated in a prospective trial.